Did α-Synuclein and Glucocerebrosidase Coevolve? Implications for Parkinson's Disease.

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Mutations in the GBA1 gene are associated with increased risk of Parkinson's disease, and the protein produced by the gene, glucocerebrosidase, interacts with α-synuclein, the protein at the center of the disease etiology. One possibility is that the mutations disrupt a beneficial interaction between the proteins, and a beneficial interaction would imply that the proteins have coevolved. To explore this possibility, a correlated mutation analysis has been performed for all 72 vertebrate species where complete sequences of α-synuclein and glucocerebrosidase are known. The most highly correlated pair of residue variations is α-synuclein A53T and glucocerebrosidase G115E. Intriguingly, the A53T mutation is a Parkinson's disease risk factor in humans, suggesting the pathology associated with this mutation and interaction with glucocerebrosidase might be connected. Correlations with β-synuclein are also evaluated. To assess the impact of lowered species number on accuracy, intra and inter-chain correlations are also calculated for hemoglobin, using mutual information Z-value and direct coupling analyses.

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